Objective: The present study combined transcriptomic data and computational techniques based on gene expression signatures to identify new bioactive compounds or Food and Drug Administration-approved drugs for the treatment of bipolar disorder (BD). Methods: Five transcriptomic datasets containing 165 blood samples from individuals with BD were selected from the Gene Expression Omnibus (GEO). The number of participants varied from six to 60, with a mean age between 35 and 48 years and a gender difference between them. Most of these patients were receiving pharmacological treatment. Master regulator analysis (MRA) and gene set enrichment analysis (GSEA) were performed to identify genes that were significantly different between patients with BD and healthy controls and their associations with mood states in patients with BD. In addition, molecules that could reverse the transcriptomic profiles of BD-altered regulons were identified from the Library of Network-Based Cellular Signatures Consortium (LINCS) and the Broad Institute Connectivity Map Drug Repurposing Database (cMap) databases. Results: MRA identified 59 candidate master regulators (MRs) that modulate regulatory units enriched with BD-altered genes. In contrast, GSEA identified 134 enriched genes and 982 regulons whose activation state was determined. Both analyses revealed genes exclusively associated with mania, depression, or euthymia, and some genes were shared among these three mood states. We identified bioactive compounds and licensed drug candidates, including antihypertensives and antineoplastic agents, as promising candidates for the treatment of BD. However, experimental validation is essential to confirm these findings in further studies. Conclusion: Although our data are still preliminary, they provide some insights into the biological patterns of different mood states in patients with BD and their potential therapeutic targets. The strategy of transcriptomics plus bioinformatics offers a way to advance drug discovery and personalized medicine by using gene expression information. Objective Administrationapproved Administration approved . (BD) Methods 16 GEO. GEO (GEO) 60 3 4 them (MRA (GSEA addition BDaltered altered NetworkBased Network Based LINCS (LINCS cMap (cMap databases Results 5 MRs (MRs contrast 13 98 determined mania depression euthymia agents However studies Conclusion preliminary targets information (BD 1 (GEO 6 9

Abstract Although widely used in medicine, separation technology, and other fields, the effects of cyclodextrins on the activities of phosphoryl transfer enzymes have not been previously evaluated. In vivo studies evaluated the function of cyclodextrins as active compounds. Despite the use of cyclodextrins as active compounds, the effects of cyclodextrins on hepatic and renal tissues remain to be fully elucidated. The primary objective of this study was to evaluate the effects of β- cyclodextrins, methyl-β-cyclodextrin (M-β- cyclodextrins), and (2-hydroxypropyl)-β-cyclodextrin (HP-β-cyclodextrins) on enzyme activities regulating the maintenance of energy homeostasis in the kidney and liver tissues in relation to toxicity. Serum levels of liver and kidney markers were measured, and oxidative stress parameters were assessed. After 60-day treatments, we observed that the administration of β-cyclodextrins and M-β-cyclodextrins inhibited the hepatic activity of pyruvate kinase, an irreversible enzyme within the glycolytic pathway. Additionally, administration of HP-β-cyclodextrins inhibited creatine kinase activity and increased the total sulfhydryl content in kidneys. Here, we demonstrated for the first time that β-cyclodextrins, M-β-cyclodextrins, and HP-β-cyclodextrins cause bioenergetic dysfunction in renal and hepatic tissues. These findings suggest that understanding the balance between cyclodextrins’ efficacy and adverse effects is essential for better accepting their use in medicine. medicine technology fields compounds elucidated β methylβcyclodextrin methyl cyclodextrin Mβ M (M-β , cyclodextrins) 2hydroxypropylβcyclodextrin hydroxypropylβcyclodextrin 2 hydroxypropyl HPβcyclodextrins HP (HP-β-cyclodextrins toxicity measured assessed 60day day 60 treatments βcyclodextrins Mβcyclodextrins pathway Additionally kidneys Here βcyclodextrins, Mβcyclodextrins, 6

Resumo Os princípios e as técnicas aplicadas na extração de DNA desempenham um papel crucial na obtenção de material genético purificado. O presente estudo investiga a eficiência de oito protocolos na extração de DNA de Hypostomus commersoni, um importante componente ictiofaunístico de riachos da América do Sul. A qualidade das amostras foi avaliada por espectrofotometria, eletroforese em gel e amplificação por marcadores de PCR-RAPD. A eficiência da extração de DNA foi influenciada tanto pelo método aplicado quanto pelo tecido-alvo de escolha. Maiores concentrações e rendimento de DNA foram obtidos a partir do tecido ocular, com um espectro positivo de incubação em tampão de lise por até 36 horas após a coleta da amostra, utilizando tecidos frescos e na presença de alta concentração de proteinase K (20 mg.ml-1). Nestas condições, as amostras foram amplificadas com sucesso. Até o momento, não há registro de descrição para os parâmetros analisados neste trabalho, nem a descrição de marcadores RAPD para a espécie H. commersoni.

Abstract The principle and the techniques applied in DNA extraction play a pivotal role in the obtention of a purified genetic material. The present study investigates the efficiency of eight protocols in the DNA extraction of Hypostomus commersoni, an essential component of South American freshwater ichthyofauna. The quality of samples was assessed through spectrophotometry, gel electrophoresis, and PCR-RAPD markers amplification. The efficiency of DNA extraction was influenced both by the method applied and the target-tissue of choice. Higher concentrations and yield of DNA were obtained from ocular tissue, with a positive spectrum of incubation in lysis buffer for up to 36 hours after sample collection, using fresh tissues and in the presence of a high concentration of Proteinase K (20 mg.ml-1). In these conditions, samples were successfully amplified. To date, there is no record of description for the parameters analyzed in this work, neither the description of RAPD markers for the species H. commersoni.

RESUMO Objetivou-se avaliar a substituição parcial da silagem de capim elefante por torta de babaçu (Orbignya speciosa) sobre o desempenho, consumo, digestibilidade, composição química e ganho em peso de carcaça de ovinos. Cinquenta e quatro machos, castrados (19,08±2,76kg) foram distribuídos em delineamento inteiramente casualizado e administrado um dos seguintes tratamentos: 0.0, 12.5, 25.0, 37.5 e 50% (%MS) de substituição da silagem pela torta de babaçu. Não houve diferença (P> 0.05) na ingestão de matéria seca, proteína bruta e fibra em detergente neutro, porém o consumo de extrato etéreo aumentou (P< 0.05). A digestibilidade da matéria seca, fibra em detergente neutro e nutrientes digestíveis totais não foram alterados, no entanto, os coeficientes de digestibilidade da proteína bruta reduziu (P< 0.05) e do extrato etéreo aumentou (P< 0.05), com a substituição. Não houve alterações no ganho de peso médio diário e ganho de peso em carcaça. Nas carcaças, observou-se aumento linear na proporção do extrato etéreo, no entanto a porcentagem de proteína bruta diminuiu. O aumento no extrato etéreo da carcaça mostrou uma tendência linear. A substituição da silagem pela torta de babaçu em até 50% não alterou o desempenho de ovinos, porém levou a aumento na deposição de gordura na carcaça.

ABSTRACT The objective of this study was to evaluate the effect of the partial replacement of elephant grass silage with babassu (Orbignya speciosa) on the performance, intake, digestibility, and carcass weight gain of sheep. Fifty-four castrated male lambs (19.08±2.76kg) were distributed in a completely randomized design and administered one of the following treatments: 0.0, 12.5, 25.0, 37.5 or 50% dry matter (%DM) replacement of elephant grass silage with babassu cake. No difference (P> 0.05) was observed in the dry matter, crude protein, and neutral detergent fiber intake, but the ether extract intake increased (P< 0.05). The digestibility of the dry matter, neutral detergent fiber, and total digestible nutrients were unaffected. The crude protein digestibility decreased (P< 0.05), and the ether extract digestibility increased with the replacement of the elephant grass. There were no changes in mean daily weight gain and carcass weight gain. In the carcasses, a linear increase was observed in the proportion of the ether extract, and the crude protein decreased. The replacement of the silage with the babassu cake by up to 50% did not change the performance of sheep, however it led to an increase in fat deposit in the carcass.

RESUMO Objetivou-se avaliar o efeito de diferentes doses de dois bioestimulantes sobre a produtividade e a estrutura do dossel do capim Urochloa brizantha cv. Marandu na fase de estabelecimento. O estudo foi realizado na Universidade Federal Rural da Amazônia, Parauapebas, Pará, Brasil. Um módulo de 35 parcelas de 25m² foi estabelecido. Utilizou-se delineamento experimental inteiramente ao acaso, composto de sete tratamentos e cinco repetições cada. Os tratamentos incluídos no controle foram: 0,5, 1 e 2kg/ha de bioestimulante A (BIOST.A); 0,25; 0,5 e 1L/ha de bioestimulante B (BIOST.B). Foram realizadas três coletas. Os dados para a aplicação dos dois bioestimulantes foram analisados separadamente, utilizando-se organização por método variável Dummy e análise de regressão. A aplicação de 2kg/ha BIOST.A resultou em incrementos de 842kg/ha na massa de forragem. A aplicação do BIOST.B na grama marandu resultou em aumento linear na produção de massa do caule. A aplicação de 2kg/ha BIOST.A no estabelecimento de erva de marandu resultou em maiores taxas de crescimento, acumulação de forragem e proporção de caule no dossel.

ABSTRACT The aim was to evaluate the effect of different doses of two biostimulants on the productivity and canopy structure of Urochloa brizantha cv. Marandu grass in the establishment fase. The study was conducted in Universidade Federal Rural da Amazônia, Parauapebas, Pará, Brazil. One module of 35 plots of 25m² were established. A completely randomized experimental design was used, with seven treatments and five replicates. The treatments included a control, 0.5, 1, and 2kg/ha of biostimulant A (BIOST.A); and 0.25, 0.5, and 1L/ha of biostimulant B (BIOST.B). Three collections were performed. The data for application of the two biostimulants were analyzed separately, using the Dummy variable method and regression analysis. The application of 2kg/ha BIOST.A resulted in increases of 842kg/ha in the forage mass. The application of BIOST.B on Marandu grass resulted in a linear increase in stem mass. The application of 2kg/ha BIOST.A in the establishment of Marandu grass result in higher growth rates, forage accumulation, and stem proportion in the canopy.

Abstract: Type 1 diabetes (T1D) is the result of the selective destruction of the pancreatic β-cells by T cells of the immune system. Although spleen is a secondary lymphoid organ, it is also involved in the T1D pathogenesis. However, the alterations in a variety of cellular processes of this disease need to be further understood. We aimed to analyze the benefits of resveratrol, and its complexed form on diabetic complications in the spleen of rats. To this end, we investigated important enzymes of phosphoryl transfer network, and Na+, K+-ATPase activity. Wistar rats were divided into non-diabetic groups: Control, Ethanol, Resveratrol, Hydroxypropyl-β-cyclodextrin, Resveratrol-hydroxypropyl-β-cyclodextrin, and diabetic groups with the same treatments. Diabetes was induced by a single dose of 60 mg/kg of streptozocin intraperitoneally, and treatments by intragastric gavage once daily for 60 days. Hyperglycemia reduced creatine kinase activity, which was reversed by the administration of resveratrol. Na+, K+-ATPase activity was greatly affected, but it was reversed by resveratrol and resveratrol-hydroxypropyl-β-cyclodextrin. This suggest an energetic imbalance in the spleen of diabetic rats, and in case this also occurs in the diabetic patients, it is possible that resveratrol supplementation could be beneficial to the better functioning of the spleen in diabetic patients.

ABSTRACT Creatine acts intracellularly as energy buffer and storage, demonstrating protective effects in animal models of neurodegenerative diseases. However, its permeability throught blood-brain barrier (BBB) is reduced. The aim of the present study was developing a carrier to facilitate the delivery of creatine to the central nervous system. Creatine nanoliposomes were produced, characterized and assayed in models of toxicity in vitro and in vivo. Particles showed negative zeta potential (-12,5 mV), polydispersity index 0.237 and medium-size of 105 nm, which was confirmed by transmission electron microscopy (TEM) images. Toxicity assay in vitro was evaluated with blank liposomes (no drug) or creatine nanoliposomes at concentrations of 0.02 and 0.2 mg/mL, that did not influence the viability of Vero cells. The result. of the comet assay that the nanoliposomes are not genotoxic, togeher with cell viability demonstrated that the nanoliposomes are not toxic. Besides, in vivo assays not demonstrate toxicity in hematological and biochemical markers of young rats. Nevertheless, increase content of creatine in the cerebral cortex tissue after subchronic treatment was observed. Altogether, results indicate increase permeability of creatine to the BBB that could be used as assay for in vivo studies to confirm improved effect than free creatine.

ABSTRACT Considering that thiol-containing enzymes like kinases are critical for several metabolic pathways and energy homeostasis, we investigated the effects of cystine dimethyl ester and/or cysteamine administration on kinases crucial for energy metabolism in the kidney of Wistar rats. Animals were injected twice a day with 1.6 µmol/g body weight cystine dimethyl ester and/or 0.26 µmol/g body weight cysteamine from the 16th to the 20th postpartum day and euthanized after 12 hours. Pyruvate kinase, adenylate kinase, creatine kinase activities and thiol/disulfide ratio were determined. Cystine dimethyl ester administration reduced thiol/disulfide ratio and inhibited the kinases activities. Cysteamine administration increased the thiol/disulfide ratio and co-administration with cystine dimethyl ester prevented the inhibition of the enzymes. Regression between the thiol/disulfide ratio, and the kinases activities were significant. These results suggest that redox status may regulate energy metabolism in the rat kidney. If thiol-containing enzymes inhibition and oxidative stress occur in patients with cystinosis, it is possible that lysosomal cystine depletion may not be the only beneficial effect of cysteamine administration, but also its antioxidant and thiol-protector effect.

Abstract Grape pomace (seed, skin and stem) is a winery byproduct with high levels of biologically active compounds, such as antioxidants and antimicrobials, that could be converted into high added-value products. Since these components are easily degraded by oxygen, light and high temperature exposure, stabilization is important, for instance, by a microencapsulation process. Therefore, the objective of this study was to investigate the influence on the particle characteristics of the operational conditions applied in the Supercritical Anti-Solvent (SAS) process for the co-precipitation of grape pomace extract and poly(-lactic-co-glycolic acid) (PLGA). The morphology and size of the particles formed, their stability and thermal profile were evaluated, and also the co-precipitation efficiency. The conditions studied allowed the production of microparticles with spherical shape for all operational conditions, with estimated particle size between 4 ± 2 and 11 ± 5 µm, and very good co-precipitation efficiencies (up to 94.4 ± 0.6%). The co-precipitated extract presented higher stability compared to the crude extract, indicating the effectiveness of the co-precipitation process and coating material against degradation processes.